Nanoparticles can be used as micro-reactor vessels, to modify the flow properties of materials, or for delivery of pharmaceutical, cosmetic or agricultural agents. In addition, formation of nanoparticles with polymers has been used in various industries to modify the miscible and volatile properties of target molecules. For instance, nanoparticles can be used to create a drug delivery system for therapeutic agents that are hydrophobic in nature and cannot be administered either orally or through intravenous injection because they are not water-soluble. Such therapeutic agents can be incorporated into nanoparticles dispersed in an aqueous solution resulting in a composition that is suitable for injection, inhalation, or oral administration. In addition, the particles can be made small enough for filtration purification and to assure that the nanoparticles will not clog capillaries or alveoli. Also, smaller particles can enhance transfer rates to the body or foliage due to the associated increase in the surface area per volume.
Some polymers have been found to be mucoadherents or have been shown to bind preferentially to mucosal linings in vitro. One such polymer contains polyacrylic acid (“PAA”), which is considered an appropriate vehicle for oral administration because when presented on the surface of a nanoparticle it demonstrates adherence to the gastro-intestinal tract and can improve drug delivery in the lower intestinal tract. PAA also demonstrates a high non-covalent affinity for vaginal mucosal lining. Mucoadhesive properties in a drug coating can be used to target a highly potent or water insoluble drugs to a targeted area in the patient. By targeting the drug to a mucosal lining, a lower dose may be administered with the same therapeutic effect. In addition, an altered water solubility of a drug should increase its bioavailability.
Additional polymers that are mucoadherents and are potential components in pharmaceutical formulations include poly(d-glucosamine), poly(d-glucaronic acid-N-acetylglucosamine), poly(N-isopropylacrylamide), poly(vinyl amine), and poly(methacrylic acid). “Mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal tract” International Journal of Pharmaceutics 177 (1999) 161-172. “Bioadhesion Technologies for the delivery of Peptide and Protein Drugs to the Gastrointestinal Tract” Critical Reviews in Therapeutic Drug Carrier Systems 11(2&3):119-160 (1994). “pH-Dependant Dissolving Nano- and Microparticles for improved Peroral Delivery of a Highly Lipophilic Compound in Dogs” AAPS PharmSci 2001; 3 (1) article 8.
Polyethylene oxide (“PEO”) is another desirable compound for use in pharmaceutical compositions. For example, liposomes with PEO on the exterior surface have been shown useful to prolong blood circulation lifetimes, decrease the rate of uptake into the mononuclear phagocyte system, and allow crossing in vivo biological bathers. PEO liposomes also have been shown to decrease the toxicity and increase the stability of an administered drug. “Interaction of PEG-Phospholipid Conjugates with phospholipid Implication in the Liposomal Drug Delivery,” Advanced Drug Delivery Reviews, 16:235-247 (1995). “Long Circulating (sterically stabilized) Liposomes for targeted drug delivery,” TiPS 15:215-220 (1994).
The formation of nanoparticles has been achieved by various methods. Nanoparticles can be made by precipitating a molecule in a water-miscible solvent, and then drying and pulverizing the precipitate to form nanoparticles. (U.S. Pat. No. 4,726,955). Similar techniques for preparing nanoparticles for pharmaceutical preparations include wet grinding or milling. Other methods include mixing low concentrations of polymers dissolved in a water-miscible solution with an aqueous phase to alter the local charge of the solvent and form a precipitate through conventional mixing techniques. (U.S. Pat. No. 5,766,635). Other methods include the mixing of copolymers in organic solution with an aqueous phase containing a colloid protective agent or a surfactant for reducing surface tension. Other methods of incorporating additive therapeutic agents into nanoparticles for drug delivery require that nanoparticles be treated with a liposome or surfactant before drug administration (U.S. Pat. No. 6,117,454).
Typically, current methods for forming nanoparticles by precipitation demonstrate little or no control of particle size and show poor yields. Uncontrolled and unpredictable particle size is particularly disadvantageous in the formation of pharmaceutical and agricultural products. Furthermore, large scale production of nanoparticles using established methods can be quite costly due to the low concentration of polymer initially introduced into the process solvent prior to nanoparticle production. Finally, many production techniques such as milling or wet grinding introduce the possibility of contamination into the final product.
In addition, methods for forming nanoparticles with additive target molecules contained within the nanoparticle typically have been performed with additives at very low ratios compared with copolymer and at low absolute concentration. Therefore, the fraction of additive target molecule per nanoparticle is minimal, and the cost of production is high. Lowering the ratio of copolymer to additive target molecule is desirable to increase the number of resulting nanoparticles that contain additive target molecule and the amount of additive target molecules contained within the nanoparticles as well as reduce the amount of initial copolymer needed to create these nanoparticles.
For the foregoing reasons, there is a need for a process of creating nanoparticles with copolymers in which the size of the resulting nanoparticle can be predicted and controlled, additives can be incorporated into the nanoparticle at a high yield, and the amount of copolymer initially needed is reduced. Furthermore, there is a long felt need for a process of producing nanoparticles at a high concentration and in which the nanoparticles produced can be harvested easily and with a high yield.